Solid and crystalline ibandronic acid

ABSTRACT

Provided are novel crystalline forms of ibandronic acid, physical data, methods for their preparation, and uses therefor. Also provided are methods for purifying and assaying ibandronic acid in any crystalline form.

RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.11/525,804, filed Sep. 22, 2006, which is a continuation of U.S. Ser.No. 11/331,995, filed Jan. 12, 2006, which is continuation ofapplication U.S. Ser. No. 11/165,481 filed Jun. 22, 2005, which claimsthe benefit of U.S. Provisional Patent Application 60/582,500, filedJun. 23, 2004, of U.S. Provisional Patent Application 60/620,016, filedOct. 18, 2004, and of U.S. Provisional Patent Application 60/690,868,Jun. 16, 2005, the contents of all of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Ibandronate Sodium is a third-generation nitrogen-containingbisphosphonate characterized by an aliphatic tertiary amine side chain.

Ibandronate Sodium is a white crystalline powder. The free acid has MW319.23 (CAS No.: 114084-78-5). The monosodium salt (anhydrous) of theacid has MW 341.23 (CAS No.: 138844-81-2). The monosodium saltmonohydrate has MW 359.23 (CAS No.: 138926-19-9).

The preparation of ibandronic acid monosodium salt is described in, forexample, U.S. Pat. No. 4,927,814. The '814 patent describes thefollowing schemes:

The preparation of ibandronic acid is taught in U.S. Pat. No. 4,927,814,wherein an ion-exchange chromatography is used in work-up. The presentinventors repeated the procedure described in the '814 patent. No solidmaterial was obtained, but an oily precipitate was the crude product.The skilled artisan knows that solids are easier to manipulate thanoils. Clearly there is a need for a method of making a solid ibandronicacid.

The monosodium salt of ibandronic acid is marketed under the trade nameBoniva®. Boniva® was developed by Hoffmann-La Roche for the treatment ofbone disorders such as: hypercalcaemia of malignancy, osteolysis,Paget's disease, osteoporosis and metastatic bone disease. Boniva® isalso marketed in Europe under the name Bondronat for cancer-related bonecomplications. Bondronat is available in ampoule with 1 ml concentratefor solution for infusion contains 1.125 mg of Ibandronic acidmonosodium salt monohydrate, corresponding to 1 mg of ibandronic acid.

Ibandronic acid can be used as an intermediate in the process for thepreparation of Ibandronate sodium.

The discovery of new polymorphic forms of a pharmaceutically usefulcompound provides a new opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has available for designing,for example, a pharmaceutical dosage form of a drug with a targetedrelease profile or other desired characteristic. There is a need in theart for polymorphic forms of ibandronic acid.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides amorphous ibandronic acid.

In another aspect, the present invention provides a method of preparingamorphous ibandronic acid that includes the step of isolating amorphousibandronic acid from an aqueous solution of ibandronic acid whichisolating step is selected from a vacuum evaporation step or alyophilization step.

In still a further aspect, the present invention relates to a method ofmaking amorphous ibandronic comprising the step of spray drying anaqueous solution of ibandronic acid.

In yet another aspect, the present invention provides solid ibandronicacid.

In one aspect, the present invention provides a process for preparingsolid Ibandronic acid comprising the steps of:

-   -   a) combining, at a temperature of about 72° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a diluent to        obtain a reaction mixture;    -   b) maintaining the reaction mixture, while heating to a        temperature of about 80° C. to about 100° C.;    -   c) further combining the reaction mixture with water, whereby        two phases, one aqueous and one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a temperature of about        95° C. to about 100° C.;    -   f) evaporating the aqueous phase to obtain a residue;    -   g) combining an alcohol with the residue to obtain whereby a        suspension is obtained; and    -   h) recovering solid ibandronic acid from the suspension, for        example by filteration or centrifugation; and optionally, drying        the recovered solid ibandronic acid

The residue of step f) may be dissolved in water prior to the additionof the alcohol in step g). After the addition of the alcohol, thereaction mixture may be heated in order to facilitate the formation ofthe precipitate.

In another aspect, the present invention provides crystalline ibandronicacid in several crystalline forms and hydrates and solvates, especiallyalcoholates, thereof. The present invention also provides ibandronicacid alcoholates.

In yet another aspect, the present invention provides a solidcrystalline form of ibandronic acid, denominated form S1, characterizedby a powder X-ray diffraction pattern having reflections at about 8.2,11.5, 11.9, 13.9, 18.6 and 22.2±0.2 deg. 2-theta. The present inventionfurther provides processes for preparing ibandronic acid form S1.

In one aspect, the present invention provides a solid crystalline formof ibandronic acid, denominated form S2, characterized by a powder X-raydiffraction pattern having reflections at about 8.1, 14.2, 16.1, 18.2and 24.4±0.2 deg. 2-theta. The present invention further provides aprocess for preparing ibandronic acid form S2.

In another aspect, the present invention provides a solid crystallineform of ibandronic acid, denominated form S3, characterized by a powderX-ray diffraction pattern having reflections at about 4.4, 8.8, 11.3,17.6 and 26.4±0.2 deg. 2-theta. The present invention further provides aprocess for preparing ibandronic acid form S3.

In yet another aspect, the present invention provides a solidcrystalline form of ibandronic acid, denominated form S4, characterizedby a powder X-ray diffraction pattern having reflections at about 4.4,8.6, 11.2, 17.3, 20.8, 22.5 and 26.0±0.2 deg. 2-theta. The presentinvention further provides a process for preparing ibandronic acid formS4.

In one aspect, the present invention provides a solid crystalline formof ibandronic acid, denominated form S5, characterized by a powder X-raydiffraction pattern having reflections at about 4.5, 8.9, 12.0, 16.0,16.3, 21.4, 22.1 and 26.9±0.2 deg. 2-theta. The present inventionfurther provides processes for preparing ibandronic acid form S5.

In another aspect, the present invention provides a solid crystallineform of ibandronic acid, denominated form S6, characterized by a powderX-ray diffraction pattern having reflections at about 5.7, 11.7, 14.3,18.5, 21.2 and 21.7±0.2 deg. 2-theta. The present invention furtherprovides processes for preparing ibandronic acid form S6.

In yet another aspect, the present invention provides a solidcrystalline form of ibandronic acid, denominated form S7, characterizedby a powder X-ray diffraction pattern having reflections at about 4.6,11.5, 16.3, 16.8, 21.0 and 22.8±0.2 deg. 2-theta. The present inventionfurther provides processes for preparing ibandronic acid form S7.

In one aspect, the present invention provides a solid crystalline formof ibandronic acid, denominated form S8, characterized by a powder X-raydiffraction pattern having reflections at about 4.5, 6.0, 11.9, 12.3,16.2, 17.8 and 21.7±0.2 deg. 2-theta. The present invention furtherprovides processes for preparing ibandronic acid form S8.

In another aspect, the present invention provides a solid crystallineform of ibandronic acid, denominated form S10, characterized by a powderX-ray diffraction pattern having reflections at about 4.8, 6.1, 12.0,12.3, 16.4, 18.0 and 21.7±0.2 deg. 2-theta. The present inventionfurther provides processes for preparing ibandronic acid form S10.

In yet another aspect, the present invention provides a solidcrystalline form of ibandronic acid, denominated form S12, characterizedby a powder X-ray diffraction pattern having reflections at about 4.7,9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3±0.2 deg. 2-theta. The presentinvention further provides a process for preparing ibandronic acid formS5.

In one aspect, the present invention provides a solid crystalline formof ibandronic acid, denominated form S13, characterized by a powderX-ray diffraction pattern having reflections at about 4.5, 8.9, 12.0,16.0, 16.3, 21.3 and 22.1±0.2 deg. 2-theta. The present inventionfurther provides processes for preparing ibandronic acid form S13.

In another aspect, the present invention provides a process forpurifying Ibandronic acid from inorganic impurities by crystallizationfrom an organic solvent selected from the group consisting of C₂₋₄alcohols and acetonitrile.

In yet another aspect, the present invention provides a HPLC method ofassaying ibandronic acid comprising the steps of: providing a samplesolution of a sample of ibandronic acid in a diluent, loading the samplesolution (ca. 50 μL) onto a 250×4.1 mm, Hamilton type PRP-X100 anionexchange column, eluting the sample from the column at 2.0 ml/min. withan eluent including nitric acid (HNO₃: 35 vol-%), potassium nitrate(KNO₃: 45 vol-%) and ethanol (20 vol-%), and measuring the ibandronicacid content of the eluent at 240 nm wavelength with a UV detector toidentify the relevant fractions.

In still a further aspect, the present invention provides A process forpurifying ibandronic acid from inorganic impurities comprising the stepsof: providing a solution of ibandronic acid containing inorganicimpurities in water or methanol; and b) combining the solution with aC₂-C₄ alcohol, especially wherein the C₂₋₄ alcohol is selected from thegroup consisting of ethanol, 1-propanol, isopropanol (EPA) andtert-butanol whereby ibandronic acid precipitates.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates an x-ray diffraction diagram of amorphous ibandronicacid.

FIG. 2 illustrates a DSC thermogram of amorphous ibandronic acid.

FIG. 3 illustrates a TGA thermogram of ibandronic acid.

FIG. 4 illustrates an x-ray diffraction diagram of ibandronic acid formS1.

FIG. 5 illustrates an x-ray diffraction diagram of ibandronic acid formS2.

FIG. 6 illustrates an x-ray diffraction diagram of ibandronic acid formS3.

FIG. 7 illustrates an x-ray diffraction diagram of ibandronic acid formS4.

FIG. 8 illustrates an x-ray diffraction diagram of ibandronic acid formS5.

FIG. 9 illustrates an x-ray diffraction diagram of ibandronic acid formS6.

FIG. 10 illustrates an x-ray diffraction diagram of ibandronic acid formS7.

FIG. 11 illustrates an x-ray diffraction diagram of ibandronic acid formS8.

FIG. 12 illustrates an x-ray diffraction diagram of ibandronic acid formS10.

FIG. 13 illustrates an x-ray diffraction diagram of ibandronic acid formS12.

FIG. 14 illustrates an x-ray diffraction diagram of ibandronic acid formS13.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides processes which utilize halo-phosphorouscompounds. Such compounds include, but are not limited to, phosphoroustrichloride, phosphorous oxychloride, phosphorous pentachloride,phosphorous tribromide, phosphorous oxybromide, phosphorouspentabromide.

In particular embodiments of the present invention, C₂-C₄ alcohols areused. The C₂-C₄ alcohols have the general structure ROH wherein R is alinear or branched alkyl group having 2 to 4 carbon atoms. Ethanol,n-propanol (1-propanol), iso-propanol (2-propanol, EPA), and t-butanol(2-methylpropan-2-ol) are preferred C₂-C₄ alcohols.

The present invention also provides processes that, in particularembodiments, utilize strong acids which do not act as oxidants foramino-phosphonic acids. Such non-oxidizing acids include, but are notlimited to, para-toluene sulfonic acid, HCl, HBr, and trichloroaceticacid.

The present invention provides amorphous ibandronic acid. Amorphousibandronic acid has an x-ray diffraction diagram not unexpected for anessentially amorphous solid. FIG. 1 shows a representative x-raydiffraction diagram of amorphous ibandronic acid.

FIG. 2 shows a representative thermogram from differential scanningcalorimetry (DSC) for amorphous ibandronic acid. The DSC thermogram doesnot exhibit any feature that can be clearly associated with afirst-order transition like crystal melting.

FIG. 3 shows a representative thermogram from thermogravimetric analysis(TGA).

Amorphous ibandronic acid can be prepared by a method that includes anisolation step. An isolation step is a step (procedure) in which asolvent, for example water is removed from a solution of ibandronic acidand can be called a “water-removal” step. This step comprises isolationof amorphous ibandronic acid from a solution of ibandronic acid in asolvent selected from the group consisting of acetonitrile (ACN),dimethylsulfoxide (DMSO), methanol, and water. Preferably, the solventis water. The isolation step can be a vacuum evaporation (i.e.concentration) step, a lyophilization step, or a spray drying step.

The term “spray drying” broadly refers to processes involving breakingup liquid mixtures into small droplets (atomization) and rapidlyremoving solvent from the mixture.

In a typical spray drying apparatus, there is a strong driving force forevaporation of solvent from the droplets, which may be provided byproviding a drying gas. Spray drying processes and equipment aredescribed in Perry's Chemical Engineer's Handbook, pgs. 20-54 to 20-57(Sixth Edition 1984).

By way of non-limiting example only, the typical spray drying apparatuscomprises a drying chamber, atomizing means for atomizing asolvent-containing feed into the drying chamber, a source of drying gasthat flows into the drying chamber to remove solvent from theatomized-solvent-containing feed, an outlet for the products of drying,and product collection means located downstream of the drying chamber.Examples of such apparatuses include Niro Models PSD-1, PSD-2 and PSD-4(Niro A/S, Soeborg, Denmark). Typically, the product collection meansincludes a cyclone connected to the drying apparatus. In the cyclone,the particles produced during spray drying are separated from the dryinggas and evaporated solvent, allowing the particles to be collected. Afilter may also be used to separate and collect the particles producedby spray drying. The process of the invention is not limited to the useof such drying apparatuses as described above.

Spray drying may be performed in a conventional manner in the processesof the present invention (see, e.g., Remington: The Science and Practiceof Pharmacy, 19th Ed., vol. 1, pg. 1627, herein incorporated byreference). The drying gas used in the invention may be any suitablegas, although inert gases such as nitrogen, nitrogen-enriched air, andargon are preferred. Nitrogen gas is a particularly preferred drying gasfor use in the process of the invention. The amorphous ibandronic acidproduct produced by spray drying may be recovered by techniques commonlyused in the art, such as using a cyclone or a filter. Spray drying ofibandronic acid from a solution of ibandronic acid in water results inamorphous ibandronic acid.

The present invention also provides solid ibandronic acid. Whenintermediate compounds are Solid substances rather than liquid, itenables the possibility of isolating and purifying the intermediate bycrystallization thereby improving the quality of the final product.

The present invention also provides solid ibandronic acid.

Solid ibandronic acid can be prepared by a process that includes thesteps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a diluent;    -   b) maintaining the reaction mixture, while heating to a        temperature of about 80° C. to about 100° C.;    -   c) combining the reaction mixture with water, whereby two phases        are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a temperature of about        95° C. to about 110° C.;    -   f) evaporating the aqueous phase to obtain a residue;    -   g) combining a C₂₋₄ alcohol or acetone with the reaction mixture        to obtain a precipitate; and    -   h) recovering the precipitate of solid ibandronic acid.

Preferably, the halo-phosphorous compound of step a) is added in smallaliquots, especially dropwise. Preferably, the diluent in step a) isselected from the group consisting of silicone oil, toluene and amixture of toluene and phosphoric acid. Preferably, the temperature instep a) is about 75° C.

Preferably, the mixture in step b) is heated to a temperature of about80° C. Preferably, the C₂₋₄ alcohol in step g) is selected from thegroup consisting of ethanol, 1-propanol, isopropyl alcohol (EPA) andtert-butanol. Most preferably, the alcohol in step g) is ethanol or IPA.The residue of step f) can be combined with water prior to the additionof the alcohol in step g). After the addition of the C₂₋₄ alcohol, thereaction mixture is optionally heated in order to facilitate theformation of the precipitate.

The present invention further provides crystalline ibandronic acid,hydrates and solvates thereof. The present invention also providesibandronic acid alcoholates. As a general rule, crystalline formspossess the advantage of being readily filterable, easily dried, andstable for extended periods of time without the need for specializedstorage conditions.

In another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated form S1, characterizedby a powder X-ray diffraction pattern having reflections at about 8.2,11.5, 11.9, 13.9, 18.6 and 22.2±0.2 deg. 2-theta. Solid crystallineibandronic acid form S1 is further characterized by X-ray powderdiffraction pattern having reflections at about 21.6, 23.8, 24.7 and28.1±0.2 deg. 2-theta. A typical x-ray diffraction diagram foribandronic acid form S1 is given in FIG. 4. Form S1 can be ahemihydrate.

Ibandronic acid form S1 can be prepared by combining an organic solventselected from the group consisting of tert-butanol, ethanol, andacetone, with an aqueous solution of ibandronic acid, and maintainingthe resulting combination for up to about 24 hours to obtain aprecipitate of ibandronic acid form S1. Preferably, the organic solventis selected from the group consisting of tert-butanol, ethanol andacetone.

Form S1 can be also prepared by combining amorphous ibandronic acid andan organic solvent at a temperature that ranges from room temperature toreflux, and maintaining the reaction mixture for a sufficient time toobtain form S1 in a slurry. Preferably, the organic solvent is selectedfrom the group consisting of tert-butanol, ethanol and acetone.

Ibandronic acid form S1 can also be prepared in a process that includesthe steps of dissolving amorphous ibandronic acid in water, addingacetone to obtain in a slurry, and stirring the slurry for a sufficienttime to obtain form S1.

Form S1 can be also prepared by a process that includes the steps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in toluene;    -   b) maintaining the reaction mixture, while heating to a        temperature of about 80° C. to about 100° C.;    -   c) removing the toluene and adding water to the reaction        mixture;    -   d) maintaining the reaction mixture at a reflux temperature;    -   e) evaporating to obtain a residue;    -   f) combining ethanol with the residue to obtain a precipitate;        and    -   g) recovering crystalline ibandronic acid form S1.

Preferably, the halo-phosphorous compound of step a) is added in smallaliquots, most preferably dropwise. Preferably, the temperature in stepa) is about 75° C. Preferably, the reaction mixture in step b) is heatedto a temperature of about 80° C.

In a further embodiment, the present invention further provides a solidcrystalline form of ibandronic acid, denominated form S2, characterizedby a powder X-ray diffraction pattern having reflections at about 8.1,14.2, 16.1, 18.2 and 24.4±0.2 deg. 2-theta. Solid crystalline ibandronicacid form S2 can be further characterized by X-ray reflections at about10.9, 19.2, 22.3, 23.3, and 28.2±0.2 deg. 2-theta. A typical x-raydiffraction diagram for ibandronic acid form S2 is given in FIG. 5.

Ibandronic acid form S2 can be prepared by providing a solution ofamorphous ibandronic acid in methanol; adding acetonitrile solvent tothe solution to obtain a slurry and recovering ibandronic acid form S2.

In a further embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated form S3, characterizedby a powder X-ray diffraction pattern having reflections at about 4.4,8.8, 11.3, 17.6 and 26.4±0.2 deg. 2-theta. Solid crystalline ibandronicacid form S3 can be further characterized by X-ray reflections at about21.6, 23.8, 24.7 and 28.1±0.2 deg. 2-theta. A typical x-ray diffractiondiagram for ibandronic acid form S3 is given in FIG. 6. Form S3 canexist as a tert-butanolate.

Ibandronic acid form S3 can be prepared by adding tert-butanol, to anaqueous solution of ibandronic acid, and maintaining the resultingmixture for at least about 24 hours or more to obtain form S3.

In another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S4, characterizedby a powder X-ray diffraction pattern having reflections at about 4.4,8.6, 11.2, 17.3, 20.8, 22.5 and 26.0±0.2 deg. 2-theta. Solid crystallineibandronic acid Form S4 can be further characterized by X-rayreflections at about 16.2, 20.5 and 21.3±0.2 deg. 2-theta. A typicalx-ray diffraction diagram for ibandronic acid Form S4 is given in FIG.7. Form S4 can be a propanolate.

Ibandronic acid Form S4 can be prepared by combining at room temperaturean aqueous solution of ibandronic acid and 1-propanol untilprecipitation occurs, and isolating Form S4. Preferably the combinationis stirred for at least about 3 hours. Optionally, the combination isheated to a reflux temperature, in order to obtain a stirrable mixture,which is then cooled to room temperature.

In yet another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S5, characterizedby a powder X-ray diffraction pattern having reflections at about 4.5,8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9±0.2 deg. 2-theta. Solidcrystalline ibandronic acid Form S1 can be further characterized byX-ray reflections at about 5.9, 10.5 and 17.8±0.2 deg. 2-theta. Atypical x-ray diffraction diagram for ibandronic acid Form S5 is givenin FIG. 8. Form S5 exists as a hemihydrate or an iso-propanolate(isopropyl alcohol solvate).

Ibandronic acid Form S5 can be prepared by a process that includes thesteps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining water with the reaction mixture, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a reflux temperature;    -   f) evaporating the aqueous phase to obtain a residue;    -   g) adding IPA to the residue,    -   h) maintaining the reaction mixture for 24 hours or more to        obtain a precipitate; and    -   i) recovering crystalline ibandronic acid Form S5.

Preferably, the halo-phosphorous compound of step a) is added in smallaliquots, most preferably dropwise. Preferably, the temperature in stepa) is about 75° C. Preferably, the reaction mixture in step b) is heatedto a temperature of about 80° C. The residue of step f) can be dissolvedin water prior to the addition of the IPA in step g). Optionally, themixture of the EPA and the residue is cooled to facilitateprecipitation.

Form S5 can be also prepared by a process including the steps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in toluene to        form a multi-phase reaction mixture    -   b) maintaining the reaction mixture, while heating to a        temperature of about 80° C. to about 100° C.;    -   c) removing the toluene, especially by decanting or any other        liquid-liquid separation technique, and combining water with the        reaction mixture;    -   d) maintaining the reaction mixture at a reflux temperature, and        evaporating to obtain a residue;    -   e) adding EPA to the residue to obtain a slurry; and    -   f) recovering crystalline ibandronic acid Form S5 from the        slurry.

Preferably, the temperature in step a) is about 75° C. Preferably, thereaction mixture in step b) is heated to a temperature of about 80° C.Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, most preferably dropwise. In addition to water, a strongacid which does not act as oxidant for amino-phosphonic acids may beadded to the reaction mixture of step c). The acid is thought tohydrolize the phosphorous intermediates that form during the previoussteps. Preferably, the acid is concentrated HCl.

Ibandronic acid Form S5 can be prepared by stirring a combination ofamorphous ibandronic acid with an organic solvent selected from thegroup consisting of tetrahydrofuran (THF) and ethanol; and recoveringForm S5. The combination is optionally heated to reflux temperature.

In another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S6, characterizedby a powder X-ray diffraction pattern having reflections at about 5.7,11.7, 14.3, 18.5, 21.2 and 21.7±0.2 deg. 2-theta. Solid crystallineibandronic acid Form S6 can be further characterized by X-rayreflections at about 14.8, 22.7, 22.8 and 30.6±0.2 deg. 2-theta. Atypical x-ray diffraction diagram for ibandronic acid form S6 is givenin FIG. 9. Form S6 can exist as a hemihydrate, tert-butanolate, or amixture of both.

Ibandronic acid Form S6 can be prepared by a process including the stepsof:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining water with the reaction mixture, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a reflux temperature;    -   f) evaporating the aqueous phase to obtain a residue;    -   g) dissolving the residue in water, followed by the addition of        tert-butanol to obtain a precipitate; and    -   h) recovering crystalline ibandronic acid Form S6.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, especially dropwise. Preferably, the temperature in stepa) is about 75° C. Preferably, the reaction mixture in step b) is heatedto a temperature of about 80° C.

Form S6 can be also prepared by a process that includes the steps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in toluene to        obtain a multiphase reaction mixture;    -   b) maintaining the reaction mixture, while heating to a        temperature of at least about 95° C.;    -   c) separating the toluene by decantation or any technique for        liquid-liquid separation, and adding an acid to the reaction        mixture;    -   d) maintaining the reaction mixture at a reflux temperature, and        evaporating to obtain a residue;    -   e) dissolving the residue in water, followed by the addition of        tert-butanol to obtain a precipitate;    -   f) recovering crystalline ibandronic acid Form S6.

Preferably, the halo-phosphorous compound of step a) is added dropwise.Preferably, the acid in step c) is a strong acid which does not act asoxidant for amino-phosphonic acids. Most preferably, the acid in step c)is concentrated HCl. Preferably, the temperature in step a) is about 75°C.

In another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S7, characterizedby a powder X-ray diffraction pattern having reflections at about 4.6,11.5, 16.3, 16.8, 21.0 and 22.8±0.2 deg. 2-theta. Solid crystallineibandronic acid Form S7 can be further characterized by X-rayreflections at about 9.0, 17.7, 19.8 and 21.8±0.2 deg. 2-theta. Atypical x-ray diffraction diagram for ibandronic acid Form S7 is givenin FIG. 10. Form S7 can exist as a hemihydrate, a 1-propanolate, or aniso-propanolate.

Ibandronic acid Form S7 can be prepared by a process including the stepsof:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining the reaction mixture with water, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a reflux temperature;    -   f) concentrating the aqueous phase to obtain a residue;    -   g) adding IPA or n-propanol ? to the residue,    -   h) maintaining the reaction mixture for less than 24 hours to        obtain a precipitate; and    -   i) recovering crystalline ibandronic acid Form S7.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, most preferably dropwise. Preferably, the temperature instep a) is about 70° C. Preferably, the reaction mixture in step b) isheated to a temperature of about 80° C.

Form S7 can be also prepared by a process including the steps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in toluene to        obtain a multiphase reaction mixture;    -   b) maintaining the reaction mixture, while heating to a        temperature of about 80° C. to about 100° C.;    -   c) separating the toluene, for example by decanting or any        technique for liquid-liquid separation, and combining water with        the reaction mixture;    -   d) maintaining the reaction mixture at a reflux temperature, and        concentrating to obtain a residue;    -   e) combining 1-propanol with the residue obtain a precipitate;    -   f) recovering crystalline ibandronic acid Form S7.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, most preferably dropwise. Preferably, the temperature instep a) is about 75° C. Preferably, the reaction mixture in step b) isheated to a temperature of about 80° C.

In yet another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S8, characterizedby a powder X-ray diffraction pattern having reflections at about 4.5,6.0, 11.9, 12.3, 16.2, 17.8 and 21.7±0.2 deg. 2-theta. Solid crystallineibandronic acid Form S8 can be further characterized by X-rayreflections at about 9.0, 16.5 and 18.9, ±0.2 deg. 2-theta. A typicalx-ray diffraction diagram for ibandronic acid Form S8 is given in FIG.11. Form S8 can be exist as an ethanolate or an iso-propanolate.

Ibandronic acid Form S8 can be prepared by a process including the stepsof:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining the reaction mixture with water, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a reflux temperature;    -   f) concentrating the aqueous phase to obtain a residue;    -   g) adding a C₂₋₄ alcohol to the residue to obtain a precipitate;        and    -   h) recovering crystalline ibandronic acid Form S8.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, most preferably dropwise. Preferably, the temperature instep a) is about 75° C. Preferably, the reaction mixture in step b) isheated to a temperature of about 80° C. The residue of step f) may bedissolved in water prior to the addition of the C₂₋₄ alcohol in step g).Preferably, the C₂₋₄ alcohol in step g) is selected from the groupconsisting of ethanol, 1-propanol and IPA. Most preferably, the C₂₋₄alcohol in step g) is ethanol.

In another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S10, characterizedby a powder X-ray diffraction pattern having reflections at about 4.8,6.1, 12.0, 12.3, 16.4, 18.0 and 21.7±0.2 deg. 2-theta. Solid crystallineibandronic acid Form S10 can be further characterized by X-rayreflections at about 18.9, 20.9 and 22.8±0.2 deg. 2-theta. A typicalx-ray diffraction diagram for ibandronic acid Form S10 is given in FIG.12. Form S10 can exist as an ethanolate.

Ibandronic acid Form S10 can be prepared by a process comprising thesteps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining the reaction mixture with water, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a reflux temperature;    -   f) concentrating the aqueous phase to obtain a residue;    -   g) adding ethanol to the residue to obtain a slurry; and    -   h) recovering from the slurry crystalline ibandronic acid Form        S110.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, most preferably dropwise. Preferably, the reactionmixture in step b) is heated to a temperature of about 80° C. Theresidue of step f) may be dissolved in water prior to the addition ofthe ethanol in step g). The reaction mixture in step g) may be seededwith amorphous ibandronic acid following the addition of the ethanol instep g).

In another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S12, characterizedby a powder X-ray diffraction pattern having reflections at about 4.7,9.0, 11.6, 20.9, 21.1, 21.7, 22.9 and 26.3±0.2 deg. 2-theta. Solidcrystalline ibandronic acid form S12 may be further characterized byX-ray reflections at about 13.8, 17.1 and 18.4±0.2 deg. 2-theta. Atypical x-ray diffraction diagram for ibandronic acid Form S12 is givenin FIG. 13. Form S12 can be a hemihydrate and/or an isopropanolate.

Ibandronic acid Form S12 can be prepared by a process including thesteps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining water with the reaction mixture, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) separating the two phases obtained;    -   e) maintaining the aqueous phase at a reflux temperature;    -   f) concentrating the aqueous phase to obtain a residue;    -   g) combining the residue with 1-propanol to obtain a        precipitate; and    -   h) recovering crystalline ibandronic acid Form S12.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, especially dropwise. Preferably, the temperature in stepa) is about 70° C. Preferably, the reaction mixture in step b) is heatedto a temperature of about 80° C.

In yet another embodiment, the present invention provides a solidcrystalline form of ibandronic acid, denominated Form S13, characterizedby a powder X-ray diffraction pattern having reflections at about 4.5,8.9, 12.0, 16.0, 16.3, 21.3 and 22.1±0.2 deg. 2-theta. Solid crystallineibandronic acid Form S13 can be further characterized by X-rayreflections at about 10.5, 17.8 and 26.9±0.2 deg. 2-theta. A typicalx-ray diffraction diagram for ibandronic acid Form S13 is given in FIG.14. Form S13 can exist as an isopropanolate.

Ibandronic acid Form S13 can be prepared by a process including thesteps of:

-   -   a) combining, at a temperature of about 70° C. to about 78° C.,        a halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride in a silicone oil        to obtain a reaction mixture;    -   b) heating the reaction mixture to a temperature of about 80° C.        to about 100° C., and maintaining while stirring;    -   c) combining the reaction mixture with water, whereby two        phases, one aqueous, one nonaqueous, are obtained;    -   d) maintaining the reaction mixture at a temperature of about        100° C.;    -   e) separating the two phases obtained;    -   f) maintaining the aqueous phase at a temperature of about        75° C. to about 100° C.;    -   g) concentrating the aqueous phase to obtain a residue;    -   h) adding EPA to the residue to obtain a precipitate; and    -   i) recovering crystalline ibandronic acid Form S13.

Preferably, the halo-phosphorous compound of step a) is added slowly, insmall aliquots, especially dropwise. Preferably, the temperature in stepa) is about 75° C. Preferably, the reaction mixture in step b) is heatedto a temperature of about 80° C.

Ibandronic acid Form S13 can be also prepared by a process including thesteps of:

-   -   a) combining, at a temperature of at least about 95° C., a        halo-phosphorous compound and phosphorous acid with        N-methyl-N-pentyl propionic acid hydrochloride to obtain a        reaction mixture;    -   b) maintaining while stirring the reaction mixture at a        temperature of about 95° C. to about 100° C.;    -   c) combining the reaction mixture with water;    -   d) cooling the reaction mixture to room temperature and        concentrating to obtain a residue;    -   e) dissolving the residue in water, followed by the addition of        IPA to obtain a precipitate; and    -   f) recovering crystalline ibandronic acid Form S13.        Preferably, the halo-phosphorous compound of step a) is added        slowly, in small aliquots, especially dropwise.

Form S13 can be also prepared by providing a solution of ibandronic acidin water at a temperature of about 38° C. to about 50°, cooling thesolution to room temperature, followed by the addition of IPA, andmaintaining the mixture at temperature for a sufficient time to obtainForm S13. Preferably, ibandronic acid is dissolved in water at atemperature of about 40° C. to provide the solution.

The following table summarizes the weight loss by TGA and water contentof the novel crystalline forms of ibandronic acid described hereinabove.

Weight loss by Water content by Form TGA [%] Karl Fisher [%] amorphous5.1 4.2 S1 3.0 7.7 1.9 2.0 2.2 2.0 5.2 2.2 2.0 1.1 1.1 S2 1.9 S3 17.80.5 S4 14.8 0.1 15.2 0.1 S5 13.0 0.7 14.1 1.1 2.7 2.3 1.2 1.1 S6 10.12.9 10.9 1.8 S7 13.4 1.2 11.4 1.9 S8 5.5 0.3 5.6 0.1 5.3 S10 5.5 0.6 S1214.0 2.4 S13 15.0 1.0 15.4

In a further embodiment, the present invention also provides a processfor purifying Ibandronic acid from inorganic impurities (i.e. reducingthe amount of inorganic impurities in) that includes the step ofdissolving ibandronic acid in water or methanol, and crystallizing byaddition of a C₂₋₄ alcohol. Preferably, the C₂₋₄ alcohol is selectedfrom the group consisting of ethanol, 1-propanol, IPA and tert-butanol.

In yet another embodiment, the present invention further provides a HPLCmethod of assaying ibandronic acid comprising the steps of: dissolvingan ibandronic acid sample in a diluent to obtain a sample solution,loading the sample solution (ca. 50 μL) onto a 250×4.1 mm, Hamilton typePRP-X100 anion exchange column, eluting the sample from the column at2.0 ml/min using a mixture of nitric acid (HNO₃: 35 vol-%), potassiumnitrate (KNO₃: 45 vol-%) and ethanol (20 vol-%) as eluent, and measuringthe ibandronic acid content of the relevant sample at 240 nm wavelengthwith a UV detector. Preferably, the diluent is water.

Some processes of the present invention involve crystallization out of aparticular solvent. One skilled in the art knows that the conditionsconcerning crystallization can be modified without affecting the form ofthe polymorph obtained. For example, when mixing ibandronic acid in asolvent to form a solution, warming of the mixture may be necessary tocompletely dissolve the starting material. If warming does not clarifythe mixture, the mixture may be diluted or filtered. To filter, the hotmixture may be passed through paper, glass fiber or other membranematerial, or a clarifying agent such as celite. Depending upon theequipment used and the concentration and temperature of the solution,the filtration apparatus may need to be preheated to avoid prematurecrystallization. The conditions may also be changed to induceprecipitation. A preferred way of inducing precipitation is to reducethe solubility of the solvent (reduce it “solubilizing power”). Thesolubility of the solvent—that is its ability to dissolve ibandronicacid—can be reduced, for example, by reducing the temperature of thesolvent.

In yet another embodiment, the present invention provides a process forpreparing ibandronate sodium (the sodium salt of ibandronic acid)comprising converting any of the solid or crystalline forms ofibandronic acid hereinabove described to ibandronate sodium by combiningthe ibandronic acid with an aqueous solution of sodium hydroxide atambient temperature (about 200 to about 28° C.), concentrating thesolution, especially at reduced pressure, to obtain a residue; combiningthe residue with acetone whereby a precipitate is formed, and recoveringibandronate monosodium.

In yet another embodiment, the present invention provides ibandronicacid having an assay of ≧99%.

In a further embodiment, the present invention provides pharmaceuticalformulations that include at least on pharmaceutically acceptableexcipient and one or more of the novel crystalline forms of the presentinvention Pharmaceutical formulations of the present invention containsolid ibandronic acid or crystalline forms thereof, such as one of thosedisclosed herein, optionally in a mixture with amorphous ibandronicacid. In addition to the active ingredient(s), the pharmaceuticalformulations of the present invention can and typically do contain oneor more pharmaceutically acceptable excipients. Such excipients areincluded in the formulations for a variety of purposes.

Diluents increase the bulk of a solid pharmaceutical composition, andmay make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelatinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol and tartaric acid.

Solid and liquid compositions (suspensions or emulsions) may also bedyed using any pharmaceutically acceptable colorant to improve theirappearance and/or facilitate patient identification of the product andunit dosage level.

In liquid pharmaceutical compositions of the present invention,ibandronic acid and any other solid excipients are suspended in a liquidcarrier such as water, vegetable oil, alcohol, polyethylene glycol,propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as guconic acid, lactic acid, citric acid oracetic acid, sodium guconate, sodium lactate, sodium citrate or sodiumacetate. Selection of excipients and the amounts used may be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges, as well as liquid syrups,suspensions and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted, or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the preparation of the composition and methods of use of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

EXAMPLES Instrumentation

X-ray diffraction data were obtained with a scintag X-Ray powderdiffractometer model X'TRA, Cu-tube, solid state detector, a roundstandard aluminum sample holder with round zero background quartz platewas used. Scanning parameters: Range: 2-40 deg.28: continues scan, Rate:5 deg./min.

DSC data were obtained with a DSC821e, Mettler Toledo instrument. Thesample weight was 3-5 mg. The heating (scan) rate was 10° C./min. Numberof holes in the crucible: 3.

TGA data were obtained using a Mettler TG50, sample weight: 7-15 mg,heating 30 rate: 10° C./min.

Karl Fischer data were obtained using a Mettler Toledo DL38, sampleweight: 100-200 mg.

Spray drying technique were obtained using “Buchi Mini Spray dryerB-290”. The spray parameters are: evaporating capacity-1 lit/hr water(higher for organic solvents); the maximum temperature input-220° C.;Air flow-max of 35 m2/hr; spray gas-compressed air or nitrogen 200-800lit/hr, 5-8 bar; Nozzel diameter-0.7 mm (standard); Nozzel cap-1.4 mmand 1.5 mm.

Example 1 Amorphous Ibandronic Acid

An aqueous solution (40% w/w) of Ibandronic acid (150 mL) was evaporatedunder vacuum (20-30 mmHg) until dryness while heating the flask in awater bath (up to 70° C.) to obtain Amorphous Ibandronic acid (67 gr).

Example 2 Amorphous Ibandronic Acid

An aqueous solution (40% w/w) of Ibandronic acid (303 gr) wasfreeze-dried (−50° C., 0.5 mmHg) for 3 days to obtain AmorphousIbandronic acid (120 gr).

Example 3 Amorphous Ibandronic Acid

Phosphorous trichloride (3.3 mL) was added to a stirred suspension ofMPPA.HCl (8 g) in silicon oil (40 mL) at 75° C. Two additional portionsof phosphorous trichloride (2×3.3 mL) were added during 2 hours afterheating the reaction mixture to 81° C. Two portions of phosphorus acid(2×3.1 g) were thereafter added during 2 hours. The reaction mixture wasstirred at 81° C. for 22 hours. Water (40 mL) was added drop-wise at 81°C. The resulting phases were separated and the aqueous phase was heatedto 90° C. for 16 hours. The obtained solution was cooled to roomtemperature and then was evaporated to obtain an oily residue. The oilyresidue was dissolved in water (7 mL) at room temperature. To theobtained solution, IPA (280 mL) was added. The obtained stickyprecipitate was heated to reflux and then was cooled to roomtemperature, after complete dissolution. Then the EPA was decanted-offand the residue was dried in vacuum oven at 50° C. for 20 hours toobtain 4.4 g of amorphous ibandronic acid.

Example 4 Amorphous Ibandronic Acid

Phosphorous trichloride (3.3 mL) was added to a stirred suspension ofMPA.HCl (8 g) in silicon oil (40 mL) at 75° C. Two additional portionsof phosphorous trichloride (2×3.3 mL) were added during 2 hours afterheating the reaction mixture to 81° C. Then two portions of phosphorusacid (2×3.1 g) were added during 2 hours. The reaction mixture wasstirred at 81° C. for 22 hours. Water (40 mL) was added drop-wise at 81°C. Then the phases were separated and the aqueous phase was heated to90° C. for 16 hours. The obtained solution was cooled to roomtemperature and then was evaporated to obtain an oily residue. The oilyresidue was dissolved in water (7 mL) at room temperature. The obtainedsolution was heated to 70° C. Then hot IPA (280 mL) (73° C.) was addeddrop-wise. The solution was cooled to room temperature. The solution wasstirred at room temperature for 21 hours. Then the IPA was decanted-offand the residue was dried in vacuum oven at 50° C. for 21 hours toobtain 4.6 g of amorphous ibandronic acid.

Example 5 Ibandronic Acid Crystal Form S1

Amorphous ibandronic acid (3.0 g) was dissolved in water (4 mL) at roomtemperature. Acetone (70 mL) was added to the stirred solution. Whiteslurry was obtained while stirring at room temperature for 68 hours. Theprecipitate was isolated by vacuum filtration, washed with acetone (2×25mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain 2.5 g ofibandronic acid crystal form S1.

Example 6 Ibandronic Acid Crystal Form S1

40% w/w aqueous solution of ibandronic acid (22.2 g) was concentratedunder vacuum. To the concentrated solution (15.71 g), tert-butanol wasadded drop-wise at room temperature in two portions (2×50 mL) and themixture was stirred at this temperature for 4 hours. The obtainedprecipitate was isolated by vacuum filtration, washed with tert-butanol(1×15 mL) and dried in a vacuum oven at 5° C. for 24 hours to obtain 5.5g of ibandronic acid crystal form S1.

Example 7 Ibandronic Acid Crystal Form S1

40% w/w aqueous solution of ibandronic acid (16.8 g) was concentratedunder vacuum. To the concentrated solution (12.1 g), absolute Ethanol(100 mL) was added drop-wise at room temperature and the mixture wasstirred at this temperature for 4.5 hours. The obtained precipitate wasisolated by vacuum filtration, washed with absolute Ethanol (2×25 mL)and dried in a vacuum oven at 50° C. for 23 hours to obtain 5.2 g ofibandronic acid crystal form S1.

Example 8 Ibandronic acid crystal Form S1

Amorphous ibandronic acid (3.0 g) was dissolved in methanol (12 mL) atroom temperature. Acetone (40 mL) was added in one portion to thestirred solution. The obtained slurry was stirred at room temperaturefor 72 hours. The resulting precipitate was isolated by vacuumfiltration, washed with acetone (2×12.5 mL) and dried in a vacuum ovenat 50° C. for 22 hours to obtain 2.5 g of ibandronic acid crystal formS1.

Example 9 Ibandronic Acid Crystal Form S1

Amorphous ibandronic acid (3.0 g) was stirred in acetone (15 mL) atreflux temperature for 5 hours. The slurry was cooled to roomtemperature and then it was stirred at this temperature for 16 hours.The product was dried in a vacuum oven at 50° C. for 24 hours to obtain2.8 g of ibandronic acid crystal form S1.

Example 10 Ibandronic Acid Crystal Form S1

Amorphous ibandronic acid (3.0 g) was stirred in absolute ethanol (20mL) at reflux temperature for 2.5 hours. The slurry was cooled to roomtemperature and then it was stirred at this temperature for 40.5 hours.The product was isolated by vacuum filtration, washed with absoluteethanol (2×20 mL) and dried in a vacuum oven at 40° C. for 25 hours toobtain 2.8 g of ibandronic acid crystal form S1.

Example 11 Ibandronic Acid Crystal Form S1

40% w/w aqueous solution of ibandronic acid (10.95 g) was concentratedunder vacuum. To the concentrated solution (7.5 g), acetone was added atroom temperature in two portions (2×45 mL) and the mixture was stirredat this temperature for 22 hours. The obtained precipitate was isolatedby vacuum filtration, washed with Acetone (2×20 mL) and dried in avacuum oven at 50° C. for 70 hours to obtain 2.9 g of ibandronic acidcrystal form S1.

Example 12 Ibandronic Acid Crystal Form S1

Phosphorous oxychloride (17 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene(70 mL) at 75° C. The reaction mixture was heated to 80° C. and wasstirred at this temperature for 26 hours. The reaction mixture wascooled to room temperature. The toluene was decanted-off and the residuewas stirred under reflux with water (70 mL) for 15.5 hours. The obtainedsolution was cooled to room temperature and then was evaporated toobtain an oily residue (34.3 g). Absolute ethanol (853 mL) was addedgradually to the oily reside while stirring at room temperature during45 hours. The obtained precipitate was isolated by vacuum filtration,washed with absolute ethanol (2×97 mL) and dried in a vacuum oven at 50°C. for 24 hours to obtain 6.7 g of ibandronic acid crystal form S1.

Example 13 Ibandronic Acid Crystal Form S2

Amorphous ibandronic acid (3.0 g) was dissolved in methanol (12 mL) atroom temperature. Acetonitrile (ACN) (40 mL) was added in one portion tothe stirred solution. The obtained slurry was stirred at roomtemperature for 72 hours. The precipitate was isolated by vacuumfiltration, washed with ACN (2×20 mL) and dried in a vacuum oven at 50°C. for 21.5 hours to obtain 2.4 g of ibandronic acid crystal form S2.

Example 14 Ibandronic Acid Crystal Form S3

40% w/w aqueous solution of ibandronic acid (11 g) was concentratedunder vacuum. To the concentrated solution (7.6 g), tert-butanol (50 mL)was added at room temperature. The obtained slurry was stirred at thistemperature for 72 hours. Then the precipitate was isolated by vacuumfiltration, washed with tert-butanol (2×40 mL) and dried in a vacuumoven at 50° C. for 22.5 hours to obtain 4.2 g of ibandronic acid crystalform S3.

Example 15 Ibandronic Acid Crystal Form S4

40% w/w aqueous solution of ibandronic acid (19.7 g) was concentratedunder vacuum. To the concentrated solution (12.5 g), 1-propanol (150 mL)was added gradually at room temperature. The un-stirrable product washeated to reflux to obtain viscous stirrable mixture. The mixture wascooled to room temperature and stirred at this temperature for 16 hours.The obtained precipitate was isolated by vacuum filtration, washed with1-propanol (2×17 mL) and dried in a vacuum oven at 50° C. for 24 hoursto obtain 6.6 g of ibandronic acid crystal form S4.

Example 16

40% w/w aqueous solution of ibandronic acid (23.7 g) was concentratedunder vacuum. To the concentrated solution (14 g), 1-propanol (100 mL)was added drop-wise at room temperature and the mixture was stirred atthis temperature for 3 hours. The obtained precipitate was isolated byvacuum filtration, washed with 1-propanol (2×35 mL) and dried in avacuum oven at 50° C. for 24 hours to obtain 10.2 g of ibandronic acidcrystal form S4.

Example 17 Ibandronic Acid Crystal Form S5

Phosphorous trichloride (10.9 mL) was added drop-wise to a stirredsuspension of MPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil(49 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×1.5 ml and 1×1 mL)were added gradually to the stirred reaction mixture at ˜80° C. Thereaction mixture was stirred at this temperature for 50 hours. Water (49mL) was added drop-wise at 79° C. The phases were separated and theaqueous phase was heated to reflux for 15.5 hours. The obtained solutionwas cooled to room temperature and then was evaporated until dryness toobtain an oily residue (27.2 g). The oily residue was dissolved in water(4 mL). To the obtained solution, IPA (209 mL) was added drop-wise atroom temperature and the mixture was stirred at this temperature for 24hours. The obtained precipitate was isolated by vacuum filtration,washed with EPA (2×52 mL) and dried in a vacuum oven at 50° C. for 24hours to obtain 9.9 g of ibandronic acid crystal form S5.

Example 18 Ibandronic Acid Crystal Form S5

Phosphorous trichloride (8.2 mL) was added drop-wise to a stirredsuspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in toluene (35mL) at 75° C. The reaction mixture was heated to 95° C. and was stirredat this temperature for 23 hours. The toluene was decanted-off and theresidue was stirred under reflux (96° C.) with 6N HCl (104 mL) for 43hours. The obtained solution was cooled to room temperature and was thenconcentrated to obtain an oily residue (8.1 g). The oily residue wasdissolved in water (4 mL). To the obtained solution, EPA (196 mL) wasadded drop-wise at room temperature and the mixture was stirred at thistemperature for 72 hours. The obtained precipitate was isolated byvacuum filtration, washed with IPA (2×40 mL) and dried in a vacuum ovenat 50° C. for 24 hours to obtain 4.5 g of ibandronic acid crystal formS5.

Example 19 Ibandronic Acid Crystal Form S5

Phosphorous oxychloride (50 mL) was added drop-wise to a stirredsuspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicone oil(210 mL) at 75° C. The reaction mixture was heated to 81° C. Twoadditional portions of phosphorous oxychloride (1×6.7 ml and 1×4 mL)were added gradually to the stirred reaction mixture at 81° C. Thereaction mixture was stirred at this temperature for 50 hours. Water(210 mL) was added drop-wise to the solution and the mixture was stirredfor 1 hr. Then the phases were separated and the aqueous phase washeated to reflux for 16.5 hours. The obtained solution was cooled toroom temperature and then was evaporated until dryness to obtain an oilyresidue (125.6 g). The oily residue was dissolved in water (19 mL). Tothe obtained solution, IPA (1760 mL) was added at room temperature andthe mixture was stirred at this temperature for 24 hours and then wascooled to 7° C. and stirred this temperature for 72 hrs. The obtainedprecipitate was isolated by vacuum filtration, washed with IPA (2×100mL) and dried in a vacuum oven at 50° C. for 25 hours to obtain 22 g ofibandronic acid crystal form S5.

Example 20 Ibandronic Acid Crystal Form S5

Amorphous ibandronic acid (3.0 g) was stirred in THF (20 mL) at refluxtemperature for 2.5 hours to obtain almost complete dissolution. Themixture was cooled to room temperature and then it was stirred at thistemperature for 21 hours. The obtained precipitate was isolated byvacuum filtration under nitrogen flow, washed with THF (2×15 mL) anddried in a vacuum oven at 40° C. for 23.5 hours to obtain 2.7 g ofibandronic acid crystal form S5.

Example 21 Ibandronic Acid Crystal Form S5

Amorphous ibandronic acid (3.0 g) was stirred in Absolute Ethanol (30mL) at room temperature. The slurry was stirred at room temperature for72 hours. The product was isolated by vacuum filtration, washed withAbsolute Ethanol (2×20 mL) and dried in a vacuum oven at 50° C. for 22hours to obtain 2.9 g of ibandronic acid crystal form S5.

Example 22 Ibandronic Acid Crystal Form S5

Phosphorous oxychloride (17 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene(70 mL) at 75° C. The reaction mixture was heated to 80° C. and wasstirred at this temperature for 26 hours. The reaction mixture wascooled to room temperature. The toluene was decanted-off and the residuewas stirred under reflux with water (70 mL) for 15.5 hours. The obtainedsolution was cooled to room temperature and then was evaporated untildryness to obtain an oily residue (34.3 g). IPA (834 mL) was addedgradually to the oily reside while stirring at room temperature during72 hours. The obtained precipitate was isolated by vacuum filtration,washed with IPA (2×84 mL) and dried in a vacuum oven at 50° C. for 23hours to obtain 12.8 g of ibandronic acid crystal form S5.

Example 23 Ibandronic Acid Crystal Form S5

Phosphorous trichloride (15.6 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in siliconoil (70 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×2 ml and 1×1.3 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 48 hours. Water (70mL) was added drop-wise at 80° C. The phases were separated and theaqueous phase was heated to reflux for 16 hours. The obtained solutionwas cooled to room temperature and then was evaporated until dryness toobtain an oily residue (38.2 g). IPA (746 mL) was added to the oilyresidue at room temperature and the mixture was stirred at thistemperature for 53.5 hours. The obtained precipitate was isolated byvacuum filtration, washed with IPA (2×83 mL) and dried in a vacuum ovenat 50° C. for 24.5 hours to obtain 11.1 g of ibandronic acid crystalform S5.

Example 24 Ibandronic Acid Crystal Form S6

Phosphorous trichloride (10.9 mL) was added drop-wise to a stirredsuspension of MPPA.HCl (7 g) and phosphorous acid (10.3 g) in siliconoil (49 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×1.5 ml and 1×1 mL)were added gradually to the stirred reaction mixture at ˜80° C. Thereaction mixture was stirred at this temperature for 50 hours. Water (49mL) was added drop-wise at 79° C. The phases were separated and theaqueous phase was heated to reflux for 15.5 hours. The obtained solutionwas cooled to room temperature and then was evaporated until dryness toobtain an oily residue (27.2 g). The oily residue was dissolved in water(3.8 mL). To the obtained solution, tert-butanol (191 mL) was added atroom temperature and the mixture was stirred at this temperature for 42hours. The obtained precipitate was isolated by vacuum filtration,washed with tert-butanol (2×38 mL) and dried in a vacuum oven at 50° C.for 25.5 hours to obtain 6.2 g of ibandronic acid crystal form S6.

Example 25

Phosphorous trichloride (8.2 mL) was added drop-wise to a stirredsuspension of MPA.HCl (7 g) and phosphorous acid (3.9 g) in toluene (35mL) at 75° C. The reaction mixture was heated to 95° C. and was stirredat this temperature for 23 hours. The Toluene was decanted-off and theresidue was stirred under reflux (96° C.) with 6H HCl (104 mL) for 43hours. The obtained solution was cooled to room temperature and then wasevaporated until dryness to obtain an oily residue (8.1 g). The oilyresidue was dissolved in water (4 mL). To the obtained solution,tert-butanol (204 mL) was added drop-wise at room temperature and themixture was stirred at this temperature for 72 hours. The obtainedprecipitate was isolated by vacuum filtration, washed with tert-butanol(2×40 mL) and dried in a vacuum oven at 50° C. for 23 hours to obtain2.8 g of ibandronic acid crystal form S6.

Example 26 Ibandronic Acid Crystal Form S7

Phosphorous trichloride (15.6 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in siliconoil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and wasstirred at this temperature for 23.5 hours. Water (70 mL) was addeddrop-wise at 80° C. Then the phases were separated and the aqueous phasewas heated to reflux for 18 hours. The obtained solution was cooled toroom temperature and then was evaporated until dryness to obtain an oilyresidue (24.5 g). IPA (443 mL) was added gradually to the oily residueand the mixture was stirred at room temperature for 18 hours. Theobtained precipitate was isolated by vacuum filtration, washed with IPA(1×80 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain9.8 g of ibandronic acid crystal form S7.

Example 27 Ibandronic Acid Crystal Form S7

Phosphorous oxychloride (17 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.8 g) in toluene(70 mL) at 75° C. The reaction mixture was heated to 80° C. and wasstirred at this temperature for 26 hours. Then the reaction mixture wascooled to room temperature. The toluene was decanted-off and the residuewas stirred under reflux with water (70 mL) for 15.5 hours. The obtainedsolution was cooled to room temperature and then was evaporated untildryness to obtain an oily residue (34.3 g). 1-Propanol (695 mL) wasadded gradually to the oily reside while stirring at room temperatureduring 18 hours. The obtained precipitate was isolated by vacuumfiltration, washed with 1-propanol (2×39 mL) and dried in a vacuum ovenat 50° C. for 24 hours to obtain 10.8 g of ibandronic acid crystal formS7.

Example 28 Ibandronic Acid Crystal Form S8

Phosphorous trichloride (18.7 mL) was added drop-wise to a stirredsuspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in siliconeoil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×2.5 ml and 1×1.5 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 51.5 hours. Water(84 mL) was added drop-wise to the solution, stirred for 15 minutes. Thephases were separated and the aqueous phase was heated to reflux for 16hours. The obtained solution was cooled to room temperature and stirredat this temperature for 12 hours. A portion (23 mL) of this solution(24.8 g) was concentrated to obtain an oily residue (11.26 g). The oilyresidue was dissolved in water (1.7 mL). To the obtained solution, IPA(87 mL) was added drop-wise at room temperature and the mixture wasstirred at this temperature for 70 hours. The obtained precipitate wasisolated by vacuum filtration, washed with IPA (2×25 mL) and dried in avacuum oven at 50° C. for 25 hours to obtain 3.27 g of ibandronic acidcrystal form S8.

Example 29 Ibandronic Acid Crystal Form S8

Phosphorous trichloride (18.7 mL) was added drop-wise to a stirredsuspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in siliconeoil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×2.5 ml and 1×1.5 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 51.5 hours. Water(84 mL) was added drop-wise to the solution and the mixture stirred for15 minutes. The phases were separated and the aqueous phase was heatedto reflux for 16 hours. The obtained solution was cooled to roomtemperature and stirred at this temperature for 12 hours. A portion (23mL) from this solution (27 g) was evaporated until dryness to obtain anoily residue (11 g). The oily residue was dissolved in water (1.6 mL).To the obtained solution, 1-propanol (160 mL) was added drop-wise atroom temperature and the mixture was stirred at this temperature for 20hours. The obtained precipitate was isolated by vacuum filtration,washed with IPA (2×10 mL) and dried in a vacuum oven at 50° C. for 25hours to obtain 3.16 g of ibandronic acid crystal form S8.

Example 30 Ibandronic Acid Crystal Form S8

Phosphorous oxychloride (20 mL) was added drop-wise to a stirredsuspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in Siliconeoil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous oxychloride (1×2.7 ml and 1×1.6 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 50 hours. Water (84mL) was added drop-wise to the solution, stirred for 20 minutes. Thephases were separated and the aqueous phase was heated to reflux for 17hours. The obtained solution was cooled to room temperature and stirredat this temperature for 12 hours. A portion (24 mL) from this solution(24 g) was concentrated to obtain an oily residue (21.65 g). The oilyresidue was dissolved in water (1.9 mL). To the obtained solution, IPA(177 mL) was added drop-wise at room temperature and the mixture wasstirred at this temperature for 23 hours. The obtained precipitate wasisolated by vacuum filtration, washed with IPA (2×20 mL) and dried in avacuum oven at 50° C. for 26.5 hours to obtain 2.37 g of ibandronic acidcrystal form S8.

Example 31 Ibandronic Acid Crystal Form S8

Phosphorous trichloride (15.6 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in siliconoil (70 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×2 ml and 1×1.3 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 48 hours. Water (70mL) was added drop-wise at 80° C. Then the phases were separated and theaqueous phase was heated to reflux for 16 hours. The obtained solutionwas cooled to room temperature and then was evaporated until dryness toobtain an oily residue (38.2 g). Absolute ethanol (766 mL) was added tothe oily residue at room temperature and the mixture was stirred at thistemperature for 53 hours. The obtained precipitate was isolated byvacuum filtration, washed with absolute ethanol (2×61 mL) and dried in avacuum oven at 50° C. for 25.5 hours to obtain 7.7 g of ibandronic acidcrystal form S8.

Example 32 Ibandronic Acid Crystal Form S8

Phosphorous trichloride (57 mL) was added drop-wise to a stirredsuspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicon oil(210 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×6.25 ml and 1×3.75 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 48 hours. Water(210 mL) was added drop-wise at 80° C. and stirred at this temperaturefor 30 minutes. Then the phases were separated and the aqueous phase washeated to reflux for 17 hours. The solution was cooled to roomtemperature and then concentrated to obtain an oily residue (121.1 g).The oily residue was dissolved in water (18 mL). Absolute ethanol (3027mL) was added to the solution at room temperature and the mixture wasstirred at this temperature for 72 hours. Cooling to 5° C. and stirringat this temperature for 7 hours. The obtained precipitate was isolatedby vacuum filtration, washed with absolute ethanol (2×48 mL) and driedin a vacuum oven at 50° C. for 23.5 hours to obtain 35.64 g ofibandronic acid crystal form S8.

Example 33 Ibandronic Acid Crystal Form S10

Phosphorous oxychloride (50 mL) was added drop-wise to a stirredsuspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicon oil(210 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous oxychloride (1×6.7 ml and 1×4 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 51 hours. Water(210 mL) was added drop-wise at 80° C. and stirred at this temperaturefor 30 minutes. Then the phases were separated and the aqueous phase washeated to reflux for 16.5 hours. The solution was cooled to roomtemperature and then was evaporated until dryness to obtain an oilyresidue (128.5 g). The oily residue was dissolved in water (19 mL).Absolute ethanol (3210 mL) was added to the solution at room temperatureand the mixture was stirred at this temperature for 39 hours. Themixture was seeded with ibandronic acid and stirred for 4.5 hours. Themixture was cooled to 0° C. and stirred at this temperature for 72hours. The obtained precipitate was isolated by vacuum filtration,washed with absolute ethanol and dried in a vacuum oven at 50° C. for 23hours to obtain 13.82 g of ibandronic acid crystal form S10.

Example 34 Ibandronic Acid Crystal Form S10

Phosphorous trichloride (15.6 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in siliconoil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and wasstirred at this temperature for 23.5 hours. Water (70 mL) was addeddrop-wise at 80° C. The phases were separated and the aqueous phase washeated to reflux for 18 hours. The obtained solution was cooled to roomtemperature and then concentrated to obtain an oily residue (24.5 g).Absolute ethanol (597 mL) was added to the oily residue and the mixturewas stirred at room temperature for 20.5 hours. The obtained precipitatewas isolated by vacuum filtration, washed with absolute ethanol (2×20mL) and dried in a vacuum oven at 50° C. for 31 hours to obtain 7.3 g ofibandronic acid crystal form S10.

Example 35 Ibandronic Acid Crystal Form S10

Phosphorous trichloride (18.7 mL) was added drop-wise to a stirredsuspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in siliconeoil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×2.5 ml and 1×1.5 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 52 hours. Water (84mL) was added drop-wise to the solution, stirred for 15 minutes. Thenthe phases were separated and the aqueous phase was heated to reflux for16 hours. The obtained solution was cooled to room temperature andstirred at this temperature for 13 hours. A portion (23 mL) from thissolution (27.31 g) was evaporated until dryness to obtain an oilyresidue (11.25 g). The oily residue was dissolved in water (1.7 mL). Tothe obtained solution, abs. ethanol (270 mL) was added drop-wise at roomtemperature and the mixture was stirred at this temperature for 20hours. The obtained precipitate was isolated by vacuum filtration,washed with abs ethanol (2×12.5 mL) and dried in a vacuum oven at 50° C.for 24 hours to obtain 8.56 g of ibandronic acid crystal form S10.

Example 36 Ibandronic Acid Crystal Form S10

Phosphorous oxychloride (20 mL) was added drop-wise to a stirredsuspension of MPA.HCl (12 g) and phosphorous acid (17.6 g) in siliconeoil (84 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous oxychloride (1×2.7 ml and 1×1.6 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 50 hours. Water (84mL) was added drop-wise to the solution, stirred for 20 minutes. Thephases were separated and the aqueous phase was heated to reflux for 13hours. The obtained solution was cooled to room temperature and stirredat this temperature for 12 hours. A portion (24 mL) from this solution(29 g) was concentrated to obtain an oily residue (12.8 g). The oilyresidue was dissolved in water (1.9 mL). To the obtained solution, abs.ethanol (300 mL) was added drop-wise at room temperature and the mixturewas stirred at this temperature for 25 hours. The obtained precipitatewas isolated by vacuum filtration, washed with abs. ethanol (2×20 mL)and dried in a vacuum oven at 50° C. for 24 hours to obtain 1.81 g ofibandronic acid crystal form S10.

Example 37 Ibandronic Acid Crystal Form S12

Phosphorous trichloride (15.6 mL) was added drop-wise to a stirredsuspension of MPA.HCl (10 g) and phosphorous acid (14.7 g) in siliconoil (70 mL) at 70° C. The reaction mixture was heated to 80° C. and wasstirred at this temperature for 23.5 hours. Water (70 mL) was addeddrop-wise at 80° C. The phases were separated and the aqueous phase washeated to reflux for 18 hours. The obtained solution was cooled to roomtemperature and then was evaporated until dryness to obtain an oilyresidue (24.5 g). 1-Propanol was added to the oily residue at roomtemperature in two portions (2×25 mL) and the mixture was stirred atthis temperature for 17.5 hours. The obtained precipitate was isolatedby vacuum filtration, washed with 1-propanol (2×20 mL) and dried in avacuum oven at 50° C. for 22.5 hours to obtain 10.1 g of ibandronic acidcrystal form S12.

Example 38 Ibandronic Acid Crystal Form S13

Phosphorous oxychloride (11.7 mL) was added drop-wise to a stirredsuspension of MPA.HCl (7 g) and phosphorous acid (10.3 g) in silicon oil(49 mL) at 75° C. The reaction mixture was heated to 80° C. Anadditional portion of phosphorous oxychloride (1×1.6 mL) was added tothe reaction mixture at 80° C. after 45.5 hours. The reaction mixturewas stirred at 80° C. for additional 2.5 hours. Water (49 mL) was addeddrop-wise at 80° C. The phases were separated and the aqueous phase washeated to 100° C. for 18 hours. The obtained solution was cooled to roomtemperature and then was concentrated to obtain an oily residue (26.7g). The oily residue was dissolved in water (4 mL). To the obtainedsolution, IPA (360 mL) was added drop-wise while stirring at roomtemperature during 48 hours. The obtained precipitate was isolated byvacuum filtration, washed with IPA (1×20 mL) and dried in a vacuum ovenat 50° C. for 24.5 hours to obtain 1.84 g of ibandronic acid crystalform S13.

Example 39 Ibandronic Acid Crystal Form S13

MPA.HCl (7 g) was added to melted phosphorous acid (3.4 g) whilestirring in an oil-bath at 95° C. Phosphorous trichloride (5.8 mL) wasadded drop-wise. The mixture was stirred at 95-100° C. (in an oil-bath)for 25.5 hours. Without cooling, but removing the oil-bath, water (21mL) was added drop-wise. The reaction mixture was stirred at 97° C. for16 hours. The obtained solution was cooled to room temperature.Insoluble particles were filtered off and the filtrate was concentratedto obtain an oily residue (12.9 g). The oily residue was dissolved inwater (1.9 mL). To the obtained solution, IPA (290 mL) was addedgradually while stirring at room temperature during 100 hours. Theobtained precipitate was isolated by vacuum filtration, washed with EPA(2×30 mL) and dried in a vacuum oven at 50° C. for 24 hours to obtain8.11 g of ibandronic acid crystal form S13.

Example 40 Ibandronic Acid Crystal Form S13

Phosphorous trichloride (50 mL) was added drop-wise to a stirredsuspension of MPA.HCl (30 g) and phosphorous acid (44 g) in silicone oil(210 mL) at 75° C. The reaction mixture was heated to 80° C. Twoadditional portions of phosphorous trichloride (1×6.25 ml and 1×3.75 mL)were added gradually to the stirred reaction mixture at 80° C. Thereaction mixture was stirred at this temperature for 48.5 hours. Water(210 mL) was added drop-wise to the solution and the mixture stirred for15 minutes. The phases were separated and the aqueous phase was heatedto reflux for 16.5 hours. The obtained solution was cooled to roomtemperature and then was concentrated to obtain an oily residue (121.3g). The oily residue was dissolved in water (18 mL). To the obtainedsolution, IPA (1698 mL) was added at room temperature and the mixturewas stirred at this temperature for 22 hours and then was cooled to 4°C. and stirred this temperature for 4 hrs. The obtained precipitate wasisolated by vacuum filtration, washed with EPA (2×43 mL) and dried in avacuum oven at 50° C. for 47 hours to obtain 39 g of ibandronic acidcrystal form S13.

Example 41 Ibandronic Acid Crystal Form S13

Ibandronic acid (97 g) was dissolved in water (90 mL) at 40° C. Thesolution was cooled to room temperature and IPA (1100 mL) was added,stirred at this temperature for 22 hrs. The obtained precipitate wasisolated by vacuum filtration, washed with IPA (2×50 mL) and dried in avacuum oven at 50° C. for 25 hours to obtain 97.6 g of ibandronic acidcrystal form S13.

Example 42 Comparative Example Repetition of Example 9 of U.S. Pat. No.4,927,814

15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphoroustrichloride in 75 ml chlorobenzene. The solvent was then decanted offand the residue was stirred under reflux with 222 ml 6N HCl for 12.5hours. Insoluble material was filtered off and the filtrate wasconcentrated and applied to column of Amberlite IR 120 (H+). The elutionwith water was monitored by HPLC. The desired fractions were combined,evaporated and stirred up with acetone to obtain a sticky oilyprecipitate as a crude product.

(The HPLC method for monitoring the ion-exchange chromatography is theone described in this application).

Example 43 Comparative Example Repetition of Example 9 of U.S. Pat. No.4,927,814—with methyl ethyl ketone used instead of acetone

15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphoroustrichloride in 75 ml chlorobenzene. The solvent was then decanted offand the residue was stirred under reflux with 222 ml 6N HCl for 12.5hours. Insoluble material was filtered off and the filtrate wasconcentrated and applied to column of Amberlite IR 120 (H+). The elutionwith water was monitored by HPLC. The desired fractions were combined,evaporated and stirred up with methyl ethyl ketone (MEK) to obtain asticky oily precipitate as a crude product. (The HPLC method formonitoring the ion-exchange chromatography is the one described in thisapplication).

Example 44 Comparative Example Repetition of Example 9 of U.S. Pat. No.4,927,814—with Acetonitrile Used Instead of Acetone

15 g N-Methyl-N-pentylaminopropionic acid (MPA.HCl) were kept for 23hours at 100° C. with 8.8 g phosphorous acid and 18.7 ml phosphoroustrichloride in 75 ml chlorobenzene. The solvent was then decanted offand the residue was stirred under reflux with 222 ml 6N HCl for 12.5hours. Insoluble material was filtered off and the filtrate wasconcentrated and applied to column of Amberlite IR 120 (H+). The elutionwith water was monitored by HPLC. The desired fractions were combined,evaporated and stirred up with acetonitrile to obtain a sticky oilyprecipitate as a crude product.

(The HPLC method for monitoring the ion-exchange chromatography is theone described in this application).

HPLC Assay

Column: Hamilton type PRP-X100, Anion exchange, 250*4.1 mm

Temp.: 35° C. Eluent: 35% HNO₃, 45% KNO₃, 20% EtOH

Flow: 2.0 mL/min

Diluent: H₂O

Injection volume: 50 μL

Detector: 240 nm

The following samples were analyzed according to the above method:

Exam- ple Crystallization % area % area % area No. medium Polymorph ofPO₄ ⁻³ of PO₃ ⁻³ of Cl⁻ 32 EtOH S8  0.4 ND* 33 EtOH S10 0.2 0.2 ND* *ND= not detected

Example 45 Amorphous Ibandronic Acid

Ibandronic acid (9 g) was dissolved in water (18 ml) at roomtemperature. The solution was divided into three portions, and eachportion was spray dried using a Buchi mini spray dryer B-290 using astandard nozzle 0.7 mm in diameter with a nozzle cap of 1.4 or 1.5 mm.The solution feed rate was about 1 L/h. The spray gas was set at 200-800L/h at a pressure of 5-8 bar. In each instance, amorphous ibandronicacid was obtained.

For portion 1, nitrogen gas was at an inlet temperature of 50° C. Theevaporated solvent and nitrogen left the spray dryer at a temperature of41-36° C.

For portion 2, nitrogen gas was at an inlet temperature of 100° C. Theevaporated solvent and nitrogen left the spray dryer at a temperature of71-72° C.

For portion 3, nitrogen gas was at an inlet temperature of 150° C. Theevaporated solvent and nitrogen left the spray dryer at a temperature of100° C.

Each of the three product was analyzed by powder x-ray diffraction andfound to be amorphous.

Example 46 Conversion of Ibandronic Acid to Monosodium Ibandronate

Ibandronic acid (4.5 g) was dissolved in water (45 ml) at roomtemperature. A solution of 1N aq. NaOH (14 ml) was added in one portion.The reaction mixture was stirred at room temperature for 2.5 hours. Thenthe solution was concentrated under reduced pressure and was poured intoAcetone (45 ml) at room temperature. A white precipitate was obtainedimmediately. The obtained slurry was stirred at room temperature for 72hours. The product was isolated by vacuum filtration, washed withAcetone (2×20 ml) and dried in a vacuum oven at 50° C. for 22 hours toobtain 4.45 g of ibandronate monosodium salt (pH=4.26).

1. A crystalline form of ibandronic acid selected from the groupconsisting of: a) the crystalline form of ibandronic acid characterizedby x-ray reflections at about 8.2, 11.5, 11.9, 13.9, 18.6, and22.2°±0.2°2θ; b) the crystalline form of ibandronic acid characterizedby x-ray reflections at about 8.1, 14.2, 16.1, 18.2, and 24.4°±0.2°2θ;c) the crystalline form of ibandronic acid characterized by x-rayreflections at about 4.4, 8.8, 11.3, 17.6, and 26.4°±0.2°2θ; d) thecrystalline form of ibandronic acid characterized by x-ray reflectionsat about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and 26.0°±0.2°2θ; e) thecrystalline form of ibandronic acid characterized by x-ray reflectionsat about 4.5, 8.9, 12.0, 16.0, 16.3, 21.4, 22.1 and 26.9°±0.2°2θ; f) thecrystalline form of ibandronic acid characterized by x-ray reflectionsat about 5.7, 11.7, 14.3, 18.5, 21.2 and 21.7°±2θ; g) the crystallineform of ibandronic acid characterized by x-ray reflections at about 4.6,11.5, 16.3, 16.8, 21.0 and 22.8°±0.2°2θ; h) the crystalline form ofibandronic acid characterized by x-ray reflections at about 4.5, 6.0,11.9, 12.3, 16.2, 17.8 and 21.7±0.2°2θ; i) the crystalline form ofibandronic acid characterized by x-ray reflections at about 4.8, 6.1,12.0, 12.3, 16.4, 18.0 and 21.7°±0.2°2θ; j) the crystalline form ofibandronic acid characterized by x-ray reflections at about 4.7, 9.0,11.6, 20.9, 21.1, 21.7, 22.9 and 26.3°±0.2°2θ; and k) the crystallineform of ibandronic acid characterized by x-ray reflections at about 4.5,8.9, 12.0, 16.0, 16.3, 21.3°±0.2°2θ.
 2. The crystalline form ofibandronic acid of claim 15 characterized by x-ray reflections at about8.2, 11.5, 11.9, 13.9, 18.6, and 22.2°±0.2°2θ, denominated form S1, andfurther characterized by x-ray reflections at about 21.6, 23.8, 24.7 and28.1°±0.2°2θ.
 3. The crystalline form of ibandronic acid of claim 16having a powder x-ray diffraction diagram substantially as shown in FIG.4.
 4. The crystalline form of ibandronic acid of claim 17, wherein thecrystalline form is hemihydrate.
 5. The crystalline form of ibandronicacid of claim 15 characterized by x-ray reflections at about 8.1, 14.2,16.1, 18.2, and 24.4°±0.2°2θ, denominated form S2, and furthercharacterized by x-ray reflections at about 10.9, 19.2, 22.3, 23.3, and28.2°±0.2°2θ.
 6. The crystalline form of ibandronic acid of claim 19having a powder x-ray diffraction diagram substantially as shown in FIG.5.
 7. The crystalline form of ibandronic acid of claim 15 characterizedby x-ray reflections at about 4.4, 8.8, 11.3, 17.6, and 26.4°±0.2°2θ,denominated form S3, and further characterized by x-ray reflections atabout 21.6, 23.8, 24.7 and 28.1°±0.2°2θ.
 8. The crystalline form ofibandronic acid of claim 21 having a powder x-ray diffraction diagramsubstantially as shown in FIG.
 6. 9. The crystalline form of ibandronicacid of claim 22, wherein the crystalline form is a tert-butanolate. 10.The crystalline form of ibandronic acid of claim 15 characterized byx-ray reflections at about 4.4, 8.6, 11.2, 17.3, 20.8, 22.5 and26.0°±0.2°2θ, denominated form S4, and further characterized by x-rayreflections at about 16.2, 20.5 and 21.3°±0.2°2θ.
 11. The crystallineform of ibandronic acid of claim 24 having a powder x-ray diffractiondiagram substantially as shown in FIG.
 7. 12. The crystalline form ofibandronic acid of claim 25, wherein the crystalline form is apropanolate.
 13. The crystalline form of ibandronic acid of claim 15characterized by x-ray reflections at about 4.5, 8.9, 12.0, 16.0, 16.3,21.4, 22.1 and 26.9°±0.2°2θ, denominated form S5, and furthercharacterized by x-ray reflections at about 5.9, 10.5 and 17.8°±0.2°2θ.14. The crystalline form of ibandronic acid of claim 27 having an x-raydiffraction diagram substantially as shown in FIG.
 8. 15. Thecrystalline form of ibandronic acid of claim 28, wherein the crystallineform is a hemihydrate or an iso-propanolate.
 16. The crystalline form ofibandronic acid of claim 15 characterized by x-ray reflections at about5.7, 11.7, 14.3, 18.5, 21.2 and 21.7°, denominated form S6, and furthercharacterized by x-ray reflections at about 14.8, 22.7, 22.8 and30.60°±0.2°2θ.
 17. The crystalline form of ibandronic acid of claim 30having a powder x-ray diffraction diagram substantially as shown in FIG.9.
 18. The crystalline form of ibandronic acid of claim 31, wherein thecrystalline form is a hemihydrate or a tert-butanolate.
 19. Thecrystalline form of ibandronic acid of claim 15 characterized by x-rayreflections at about 4.6, 11.5, 16.3, 16.8, 21.0 and 22.8°±0.2°2θ,denominated form S7, and further characterized by x-ray reflections atabout 9.0, 17.7, 19.8 and 21.8°±0.2°2θ.
 20. The crystalline form ofibandronic acid of claim 33 having a powder x-ray diffraction diagramsubstantially as shown in FIG.
 10. 21. The crystalline form ofibandronic acid of claim 34, wherein the crystalline form is ahemihydrate, a 1-propanolate, or an iso-propanolate.
 22. The crystallineform of ibandronic acid of claim 15 characterized by x-ray reflectionsat about 4.5, 6.0, 11.9, 12.3, 16.2, 17.8 and 21.7±0.2°2θ, denominatedform S8, and further characterized by x-ray reflections at about 9.0,16.5 and 18.9°±0.2°2θ.
 23. The crystalline form of ibandronic acid ofclaim 36 having a powder x-ray diffraction diagram substantially asshown in FIG.
 11. 24. The crystalline form of ibandronic acid of claim37, wherein the crystalline form is an ethanolate or an iso-propanolate.25. The crystalline form of ibandronic acid of claim 15 characterized byx-ray reflections at about 4.8, 6.1, 12.0, 12.3, 16.4, 18.0 and21.7°±0.2°2θ, denominated form S10, and further characterized by x-rayreflections at 18.9, 20.9 and 22.8°±0.2°2θ.
 26. The crystalline form ofibandronic acid of claim 39 having a powder x-ray diffraction diagramsubstantially as shown in FIG.
 12. 27. The crystalline form ofibandronic acid of claim 41, wherein the crystalline form is anethanolate.
 28. The crystalline form of ibandronic acid of claim 15characterized by x-ray reflections at about 4.7, 9.0, 11.6, 20.9, 21.1,21.7, 22.9 and 26.3°±0.2°2θ, denominated form S12, and furthercharacterized by x-ray reflections at about 13.8, 17.1 and 18.4°±0.2°2θ.29. The crystalline form of ibandronic acid of claim 42 having a powderx-ray diffraction diagram substantially as shown in FIG.
 13. 30. Thecrystalline form of ibandronic acid of claim 43, wherein the crystallineform is a hemihydrate or an iso-propanolate.
 31. The crystalline form ofibandronic acid of claim 15 characterized by x-ray reflections at about4.5, 8.9, 12.0, 16.0, 16.3, 21.3°±0.2°2θ, denominated from S13, andfurther characterized by x-ray reflections at about 10.5, 17.8 and26.9°±0.2°2θ.
 32. The crystalline form of ibandronic acid of claim 45having a powder x-ray diffraction diagram substantially as shown in FIG.14.
 33. The crystalline form of ibandronic acid of claim 46, wherein thecrystalline form is an iso-propanolate.